Inhalable drug delivery, where an aerosolized pharmaceutical formulation is orally or nasally inhaled by a patient to deliver the formulation to the patient's respiratory tract, has proven to be a particularly effective and/or desirable alternative to other forms of drug delivery. Many types of inhalation devices exist including devices that aerosolize a dry powder pharmaceutical formulation.
One type of dry powder inhalation device aerosolizes a pharmaceutical formulation that is stored in a unit dose receptacle, such as a capsule or a blister package. A dose or a portion of a dose of a dry powder pharmaceutical formulation may be stored in the receptacle, and the receptacle may be inserted into an aerosolization device which is capable of removing the dry powder from the receptacle and aerosolizing the pharmaceutical formulation. In capsule-based dry powder inhalers, the capsule itself is often used to help effectively aerosolize the powder.
In another type of dry powder inhaler, the dry powder may be contained within a receptacle that is integrated within the device or that is insertable into the device. In this type of device, the receptacle is stationary within the device. One particular type of insertable receptacle is a blister pack. In one form, a blister pack is insertable into a passive dry powder inhaler where a user's inhalation is used to aerosolize the powder, an example of which is described in US Patent Application Publication 2010/0108058 (Glusker et al.), which is incorporated herein by reference in its entirety for all purposed. In another form, a blister pack is insertable into an active dry powder inhaler where additional energy is used for aerosolization, such as the one described in U.S. Pat. No. 5,740,794, where compressed air is released to provide the powder aerosolization energy. U.S. Pat. No. 5,740,794 is also incorporated herein by reference in its entireties for all purposes.
In all types of dry powder inhalers, the size and quality of the dose delivered to the user is dependent on the amount and condition of aerosolizable pharmaceutical formulation that exits the device. In conventional dry powder inhalers, the amount and condition of the aerosolizable pharmaceutical formulation may vary from use to use and/or from user to user. For example, often powder may exit a receptacle in agglomerated form creating particles that are too large to be effectively and consistently administered to the respiratory tract.
The effectiveness and consistency of the aerosolization and deagglomeration of the powder depends in large part on the inhalation energy provided, which is often provided by the user's inhalation. If there is not a sufficiently high flow rate through the receptacle, there is a risk that the powder will not be effectively and consistently deagglomerated into desirably sized particles. The required inhalation energy for powder fluidization and dispersion is dependent on the nature of the formulation, and in particular the adhesive forces of the drug particles to carrier particles, walls of the inhaler, or other drug particles.
There has been considerable focus recently on the adverse impact that incorrect inhaler use has on disease management in patients with asthma, chronic obstructive pulmonary disease (COPD), and other respiratory diseases. Improved training is viewed as important. Written instruction alone, as provided in the instructions for use, is viewed as inadequate. Verbal instruction is better, but this necessitates dedicated resources, which are becoming increasingly difficult to realize in a cost-constrained market. Thus, there is a need for an engineered device which requires minimal training, and minimizes the impact of poor inhaler technique on aerosol performance.
Some inhaler errors are defined as critical if they can substantially impact dose delivery to the lungs. In a large study involving 3811 patients, it was found that about half of the subjects had at least one such critical error. Critical errors may be classified into three categories: (a) failure-to-use errors; (b) dose preparation errors, and; (c) dose inhalation errors.
Failure-to-use errors are related to a number of diverse factors. Poor regimen compliance, also known as adherence, is common to all therapeutic areas. Poor compliance does not correlate with age, socioeconomic status, sex, disease severity, risk of death or knowledge of disease. Failure-to-use errors include simply forgetting, a desire to not be on a regular medication, a failure to understand the importance of regular therapy, or a feeling of well being (no longer need the drug). There are also failure-to-use errors related to the costs of treatment, and the complexity of the treatment regimen, which may require the patient to inhale multiple medications from multiple devices, multiple times daily. Fixed dose combinations comprising bronchodilators and inhaled corticosteroids in a single inhaler (e.g., Advair®, GSK), simplify the treatment regimen, thereby improving patient compliance. Fixed dose combinations comprising once daily medicines may further help in this regard.
Dose preparation errors are related to the number and complexity of steps required to prepare the dose to be inhaled. These errors are highly device dependent. Poor device compliance may be due to a lack of competence (i.e., the inability to use the device correctly) or contrivance (i.e., having the competence to use the device correctly, but contriving to use it in a manner that fails to effectively deliver drug to the lungs). In their simplest form, device use instructions may be “open-inhale-close”, where the inhalation maneuver triggers dose preparation (i.e., breath actuation). In currently marketed multi-dose dry powder inhalers (MD-DPI), an additional step to prepare the dose is required. In Diskus® (Glaxo Smith Kline), this involves moving a lever, while in Turbuhaler® (Astra-Zeneca), it requires a twist of the device. Optimally, devices must be developed with the intended patient population, dose and regimen in mind. For example, a three step “open-inhale-close” device is impractical for the delivery of tobramycin to cystic fibrosis patients, owing to the large nominal dose.
Dose inhalation errors include device-independent and device-dependent errors. Device-independent errors include errors related to the instructions for use (e.g., failure to exhale before inhalation, and failure to breath-hold). These are in fact, the two most common critical errors observed. Device-dependent errors include errors related to variations in the inhalation profile (e.g., peak inspiratory flow rates too low to achieve effective powder deagglomeration), inhaled volumes too small to empty the powder contents from a receptacle, or poor coupling of the inhalation profile to the powder emptying event from a receptacle.
Poor adherence is common to all therapeutic areas. Poor adherence may result from simply forgetting to take a dose, or psychological/cognitive factors such as: a desire to not be on a regular medication, a failure to understand the importance of regular therapy, or a feeling of well-being (no longer needing the drug). Confidence that the dose has been delivered as intended via visual, auditory, or other sensory feedback has been the subject of various schemes. In some cases, the rapid onset of a pharmacologic effect provides direct confirmation of drug delivery. The situation is far more complex for the delivery of an inhaled corticosteroid from a multi-dose dry powder inhaler. In this case, there is no immediate pharmacologic effect, and sensory feedback is also limited. Dose confirmation must rely on indirect measures of pressure, or airflow through the device. Such measurements carry the risk of false positives. The more reliable an inhaler and drug combination, especially one wherein particle delivery is largely independent of flow rate, ramp time, inhaled volume and peak inspiratory flow, can substantially mitigate the types of patient errors that lead to a requirement for adherence or compliance monitoring.
Parameters which define the inhalation profile are shown in FIG. 1. Subjects use muscles in their diaphragm to create a negative pressure in the inhaler. The maximum inspiratory pressure (MIP) is not strongly correlated with the severity of lung disease. A better correlation is observed with a subject's age, with the youngest and oldest of subjects unable to generate as high a MIP. While patients may be able to generate high MIP values when asked to inhale forcefully through a device, they will often later revert to breathing comfortably through a device in practice.
The peak inspiratory flow rate (PIF) depends on the subject's inspiratory effort (e.g., forceful or comfortable as described above) and the resistance of the device. The relationship between device resistance (R), pressure drop across the inhaler (ΔP), and flow rate (Q) is given by equation 1:
                    Q        =                                            Δ              ⁢                                                          ⁢              P                                R                                    (        1        )            
Other parameters in the inhalation profile include the inhaled volume (Vi), the ramp time to 60% of peak flow (t60), and the total inhalation time (ti). The inhaled volume varies with a subject's age and the severity of their disease. One consideration for a device is that there is sufficient inhaled volume to deliver the dispersed powder to the bronchial airways. This includes airflow to empty the powder from the powder receptacle, and sufficient chase air to deposit the drug past the subject's oropharynx (mouth and throat). The ramp time is another consideration for devices, such as blister-based devices, in which powder emptying from the receptacle occurs very early in the inhalation profile, before peak flow rates have been established. Often powder emptying is complete before peak flows and optimal dispersing energy is attained within the device.
Therefore, it is desirable to provide a device or a particulate powder formulation/inhaler device combination which reduces dose inhalation errors. In this regard, it is still further desirable to provide aerosol delivery to a patient's lungs which is largely independent of the subject's inhalation profile in terms of ramp rate to peak flow, flow rate, and inhaled volume.
It is also desirable to be able to aerosolize a powder pharmaceutical formulation in a consistent manner. It is also desirable to be able to aerosolize a pharmaceutical formulation in a highly deagglomerated form and/or with improved aerosol characteristics. It is further desirable to assure deagglomeration and improved aerosol characteristics in an easily manufacturable and usable aerosolization device. It is still further desirable to provide an aerosolization device that affords improved matching of peak inhalation flow to powder aerosolization and receptacle emptying resulting in a greater amount of powder being emptied during the highest inhalation flow rates, thus providing greater dispersion energy and concomitant better lung delivery. It is still further desirable to be able to accomplish the above in a blister-based, passive dry powder inhaler.